U.S. Mifepristone Clinical Trial: Summary of Findings

Early
pregnancy termination with mifepristone and misoprostol in the United States, Irving M.
Spitz, M.D. D.Sc., C. Wayne Bardin, M.D., Lauri Benton, M.D., and Ann Robbins, Ph.D., New
England Journal of Medicine, April 30, 1998 and

Acceptability and feasibility of early pregnancy
termination by mifepristone-misoprostol: Results of a large multi-center trial in the
United States, Beverly Winikoff, M.D., M.P.H., Charlotte Ellertson, Ph.D., Batya Elul,
M.Sc., and Irving Sivin, M.A., Archives of Family Medicine, July/August 1998

Highlights

The U.S. study of mifepristone medical abortion was a success:

The method was provided safely and effectively within the diverse U.S. healthcare
system.

Even with a rigorous definition of success, the efficacy in providing abortions up to 49
days was comparable to the European experience.

Nearly all of the women in the study reported they would recommend medical abortion to
others and that they would choose it again, if necessary

Almost three-quarters of the women who had had a previous surgical abortion said medical
abortion was more satisfactory.

Providers' feedback suggests that efficacy increases as physicians, nurses, and
counselors gain experience and comfort with the method. This finding reinforces the need
for extensive physician information and education.

Goals of the U.S. clinical trials

The U.S. trials were conducted:

to see whether the regimen could be provided safely and effectively within the U.S.
healthcare system;

to confirm the French data, which showed the mifepristone-misoprostol combination was
safe and effective up to 49 days from the beginning of the last menstrual period; and

to gain experience and test safety and efficacy of use up to 63 days.

Sites and women were diverse and inclusive

2121 women age 18 and older took part in the study at 17 sites around the United States.

The women in our study were from a mix of economic and ethnic backgrounds, including
Caucasian, African American, Hispanic, and Asian.

The clinic locations spanned the nation and included free-standing clinics, Planned
Parenthood clinics, and university hospitals.

Medical abortion can be provided safely and well in the U.S.

Despite its mix of providers (clinics and private practices), the U.S. healthcare
delivery system can provide this form of medical abortion safely and well. (Other
countries in which this drug has been approved-France, United Kingdom, and Sweden-have
medical systems that provide access to abortions at more standardized delivery sites.)

Although the regimen called for multiple visits, women understood the need to return for
the second drug and follow-up examinations.

All side effects experienced were the same as in other countries. All side effects were
expected.

Efficacy results up to 49 days with mifepristone and misoprostol are comparable to
other studies

Up to 49 days, efficacy was 92 percent, compared to the 95 percent that is commonly
cited in the European experience. The success rate declines with advancing gestational
age.

The ongoing pregnancy rate for women under 49 days gestation was low: one percent fell
into this category, the same as in French studies. Ongoing pregnancy increased with
gestational age.

In the U.S. clinical trials, success rates for women who underwent medical abortion at
later gestational ages were 83 percent for 50 to 56 days and 77 percent for 57 through 63
days.

75 percent of women who had successful abortions had them within 24 hours after
misoprostol administration.

Side effects are similar to a natural miscarriage

The most frequent side effects were those a woman would experience with a natural
miscarriage-bleeding and cramping. Almost all women experienced these two effects.

Other studies have shown that the actual amount of blood lost during surgical and
medical abortions for gestational ages less than 49 days is about the same, and in either
case, is generally not clinically significant.

The median duration of bleeding and spotting was 13 days in the less-than-49-days group
and 15 days in later groups. By the end of the two-week study period, most of the reported
bleeding was due to spotting.

Gastrointestinal side effects of the drugs, such as nausea, diarrhea, and vomiting
mostly took place in the four hours following ingestion of the second drug, misoprostol.
Nausea increased with gestational age. Sixty-eight percent of the women in the U.S. trial
were given medication (mostly acetaminophen) for their pain.

Fifty-six women required surgical intervention for excessive bleeding. Four women
received blood transfusions, identical to the French experience.

Any physician or hospital emergency room experienced in treating women with miscarriages
should be able to treat a woman with a bleeding problem related to her medical abortion.

Women were highly satisfied with the procedure

96 percent of the women in the study said they would recommend it to others; 91 percent
would choose it again; and 88 percent found it very or moderately satisfactory.

Even among women for whom the method failed, 70 percent would try it again; 85 percent
would recommend it to others; and 52 percent found it very or moderately satisfactory.

Among women whose experience differed from their expectations, two-thirds felt the
experience was better than expected, while one-third thought it was worse.

More than three-quarters of the women who had had a previous surgical abortion-about
half of the total sample of women-said medical abortion was more satisfactory. Even among
patients who had method failures, 45 percent felt the failed medical abortion had been
more satisfactory than their previous surgical abortion.

African Americans, Caucasians, Asians, and Hispanics had comparable, high satisfaction
ratings of the method

Women cited as the best features of the method: no surgery and/or injections,
noninvasive; natural, feminine, like menses or miscarriage; less pain; easier emotionally,
less frightening; and easier, simpler, or faster.

Women cited as the worst features of the method; feared or actual pain or cramping,
waiting, uncertainty, or fear of the unknown; feared or actual nausea, vomiting, or
diarrhea. Twenty-two percent said that there had been no worst features at all.

Rigorous definition of failure affected study results

We had a rigorous definition of failure. We considered the method a failure if a woman
chose to try medical abortion but then had a surgical intervention during the study
period-for any reason at all. In other words, success meant no surgery during the study
period. Failure under this definition resulted if a surgical procedure was used for any of
these reasons:

The drugs failed to terminate a pregnancy;

The patient asked for a surgical abortion (for example, one woman had to go out of town
and couldn't return for the second visit). Other studies might consider women who withdraw
from a trial as dropouts and exclude them from analysis; we kept them in our study and
considered that the method had failed for them;

The physician intervened, even though surgery was not (in hindsight) essential;

The drugs created a medical need to intervene;

The abortion was incomplete, in that some tissue remained in the uterus and the
physician thought that surgery was the best way to manage the situation;

The abortion was not complete at day 15 (had the protocol allowed the providers to
continue waiting, the abortion might have occurred later without surgical intervention).

Provider experience is key to successful outcome

The various studies of the mifepristone-misoprostol regimen produce different rates of
success and failure. Why might the success rate from this U.S. clinical trial be somewhat
lower than the results from the latest French study? The drug combination is the same; the
difference may lie in the providers' experience. Although this study was not designed to
test whether success rates improved with provider experience, clinicians associated with
the trial report that their success rate increased as they became more comfortable with
the method.

Physicians who are not used to providing medical abortion are more likely to intervene
surgically for bleeding.

Over time physicians learn how to counsel patients better about what to expect from the
method, and to reassure them if they are worried.

General Information about Mifepristone in the United States

Were any U.S. government funds used for this project?

No government funds were used for these trials or any other part of the project.

What does the approval process involve?

The U.S. rights were donated to the Population Council in May 1994. Our clinical trial
started in September 1994 and concluded a year later. The 164-volume NDA, which was
submitted in March 1996, was based on data from the French pivotal studies, which we
translated, audited, and re-analyzed. In July, after a public hearing, an FDA advisory
committee recommended that the FDA approve use of mifepristone for medical abortion. The
FDA issued an approvable letter in September 1996, saying that mifepristone was safe and
effective, but that the Council needed to provide additional information on labeling and
manufacturing. Since then, we have given the agency revised labeling and four volumes with
the U.S. clinical trial data. In June 1997, we gave the FDA a safety update on all
worldwide experience on the use of mifepristone for all indications. Additional
information on manufacturing still has to be provided before the drug can be approved

Is it unusual for the FDA to approve a drug based on data from other countries?

No. The FDA routinely approves drugs already approved by regulatory agencies in Europe.
The New Drug Application for mifepristone was based on good-quality French studies and
extensive additional data from Europe and around the world. The FDA requires NDA sponsors
(the Council in this case) to provide all information related to safety regardless of the
geographic source.

When will mifepristone be available in the U.S.?

Our licensee, The Danco Group, has said it expects the drug to be approved and
available in 1999.

How much will the mifepristone-misoprostol regimen cost when it is available?

It is not yet possible to determine the cost. In general use, we believe the cost of
medical abortion will be comparable to surgical abortion. The cost of the pills themselves
is only one factor in overall cost determination. Our distributor also plans to make the
drug accessible to women with limited financial resources through Medicaid where
available.

Who will be able to provide mifepristone?

Any properly trained provider, working in a hospital, clinic, or office setting, with
access to backup facilities for treating incomplete abortion and medical emergencies, will
be able to provide mifepristone. Providers must be able to date a pregnancy and detect an
ectopic pregnancy. Mifepristone will not be available at commercial pharmacies.

Will young women have access to this drug?

Once it is approved by the FDA, physicians will be able to prescribe the drug for women
of any age who do not have medical contraindications to it, in accordance with state laws.

Will availability of mifepristone eliminate the need for surgical abortion?

Mifepristone is effective only during early pregnancy. Surgical abortion will still be
needed for the small number of cases where mifepristone fails; for later abortions; and as
an option for women who prefer it.

How will mifepristone change the abortion picture?

Abortion may be more accessible and more private. We expect that women will be able to
locate providers closer to their homes who are willing to provide nonsurgical abortions.
Eventually, women obtaining medical abortions may have greater privacy than women
undergoing surgical abortions. In addition, over time, women will become more accustomed
to seeking their abortions earlier in pregnancy. We do not anticipate an increase in the
number of abortions; in France, for example, the total number of abortions per year has
not increased since the method was introduced in 1989.

The Population
Council is a nonprofit, nongovernmental institution that seeks to improve the wellbeing
and reproductive health of current and future generations around the world and to help
achieve a humane, equitable, and sustainable balance between people and resources. The
Council conducts biomedical, social science, and public health research and helps build
research capacities in developing countries. Established in 1952, the Council is governed
by an international board of trustees. Its New York headquarters supports a global network
of regional and country offices